Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis (NASH) of which many develop hepatic injury that may progress to cirrhosis. We have previously shown that in chronic cholestatic liver diseases, cholangiocytes, through the products of their cellular activation such as secretin (SCT), are the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. We have also demonstrated that activation of the SCT/SR axis plays a key role in the progression of liver fibrosis and biliary damage during cholestasis in animal models and human liver samples via secretion of transforming growth factor-b1 (TGF-b1) by cholangiocytes and subsequent activation of hepatic stellate cells (HSCs). Recent evidence and our novel preliminary data indicate that cholangiocytes play a key role in the pathogenesis of NAFLD/NASH through activation of biliary damage/proliferation and subsequent liver fibrosis. Our preliminary data that the SCT/secretin receptor (SR) axis is upregulated in cholangiocytes in an animal model of NAFLD/NASH and human liver samples with steatosis and steatohepatitis support the concept that the SCT/SR axis plays a key role in the progression of NAFLD and NASH. Based upon these findings, we propose the central hypothesis that the SCT/SR axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) activation of the SCT/SR axis stimulates a neuroendocrine/profibrogenic biliary phenotype in response to FFA-induced biliary damage triggering the activation of HSCs via a paracrine TGF-b1-dependent mechanism; and (ii) inhibition of the SCT/SR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype and hepatic steatosis and fibrosis during the progression of NAFLD/NASH. Completion of the proposed studies will provide a translational mechanism of how activation of the SCT/SR axis promotes local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype and hepatobiliary steatosis and fibrosis during the progression of NAFLD/NASH.!